Nitric oxide mediates collecting duct endothelin‐1 effects on blood pressure

Abstract

Collecting duct (CD)-derived endothelin-1 (ET-1) modulates systemic blood pressure (BP) and Na excretion, but the mechanisms by which ET-1 exerts these effects are poorly understood. To address this, mice with CD-specific ET-1 knockout (CD ET-1 KO) and controls were studied (n=6–8). On a normal (0.3%) Na diet, systolic BP (radiotelemetry) in CD ET-1 KO mice was 19 ± 3 mmHg greater than controls. L-NAME (1 mg/ml drinking water) administration for 3 days increased BP in CD ET-1 KO by 11 ± 2 mmHg and in control mice by 28 ± 4 mmHg, thereby abolishing the difference in BP between the two groups. High (4%) Na diet ± L-NAME increased BP by 10 ± 3 mmHg in both groups. Urinary nitric oxide (NO) (nitrate+nitrite) excretion was reduced by 23 ± 4 % in CD ET-1 KO, as compared to control, mice on a normal or high Na diet. In acute studies wherein renal perfusion pressure was controlled at two different levels, urine volume and NO excretion rate were reduced in CD ET-1 KO mice as compared to controls at both perfusion pressures. Measurement of NO synthase (NOS) 1, 2 and 3 activity in inner medullae revealed reduced NOS3 activity in CD ET-1 KO mice on a normal Na diet, while NOS1 and NOS3 activities were decreased in CD ET-1 KO mice on a high Na diet when compared to control mice, respectively. In conclusion, these data suggest that hypertension in CD ET-1 KO mice is due to reduced renal NO production, the latter due, at least partially, to decreased medullary NOS activity.